Epigenetic hallmarks of age-related macular degeneration are recapitulated in a photosensitive mouse model

Age-related macular degeneration (AMD) is a chronic, multifactorial disorder and a leading cause of blindness in the elderly. Characterized by progressive photoreceptor degeneration in the central retina, disease progression involves epigenetic changes in chromatin accessibility resulting from environmental exposures and chronic stress. Here, we report that a photosensitive mouse model of acute stress-induced photoreceptor degeneration recapitulates the epigenetic hallmarks of human AMD. Global epigenomic profiling by assay for transposase-accessible chromatin using sequencing (ATAC-Seq) revealed an association between decreased chromatin accessibility and stress-induced photoreceptor cell death in our mouse model. The epigenomic changes induced by light damage include reduced euchromatin and increased heterochromatin abundance, resulting in transcriptional and translational dysregulation that ultimately drives photoreceptor apoptosis and an inflammatory reactive gliosis in the retina. Through our findings, we identified key histone-modifying enzymes that contribute to the observed changes in global chromatin accessibility. Moreover, pharmacological inhibition of histone deacetylase 11 (HDAC11) and suppressor of variegation 3-9 homolog 2 (SUV39H2) ameliorated light damage in our mouse model, supporting a causal link between decreased chromatin accessibility and photoreceptor degeneration, thereby representing a potential new therapeutic strategy to combat AMD. RNA-seq and ATAC-seq was conducted on C57BL/6J abca4-/- rdh8-/- mice in replicates of 3-4. ------------------------------------------------- *This submission lacks processed data for the ATAC-Seq component年龄相关性黄斑变性（Age-related macular degeneration, AMD）是一种慢性、多因素疾病，亦是老年人失明的首要病因。该病以视网膜中央区域感光细胞进行性退化为核心特征，疾病进展过程涉及环境暴露与慢性应激所引发的染色质可及性表观遗传改变。本研究构建了急性应激诱导感光细胞变性的光敏小鼠模型，该模型可复现人类AMD的表观遗传标志性特征。本研究通过转座酶可及性染色质测序（assay for transposase-accessible chromatin using sequencing, ATAC-Seq）开展全基因组表观组分析，结果显示，该小鼠模型中染色质可及性降低与应激诱导的感光细胞死亡存在显著关联。光损伤所诱导的表观组改变包括常染色质丰度降低与异染色质丰度升高，由此引发转录与翻译失调，最终驱动感光细胞凋亡以及视网膜内的炎症反应性胶质增生。通过本研究的实验结果，我们鉴定出了参与全局染色质可及性改变的关键组蛋白修饰酶。此外，对组蛋白去乙酰化酶11（histone deacetylase 11, HDAC11）与染色质沉默因子3-9同源物2（suppressor of variegation 3-9 homolog 2, SUV39H2）进行药理学抑制，可减轻该小鼠模型的光损伤程度，证实了染色质可及性降低与感光细胞变性之间的因果关联，由此为对抗AMD提供了潜在的全新治疗策略。本研究对C57BL/6J abca4-/- rdh8-/-小鼠开展了RNA测序（RNA-seq）与转座酶可及性染色质测序（ATAC-Seq），每组设置3~4次生物学重复。 *本次提交缺少ATAC-Seq组件的处理后数据